1. Field of the Invention
The present application relates to process of making 2-deoxy-2,2-difluoro-D-ribofuranosyl nucleosides, such as gemcitabine, intermediates therefor, and process of making the intermediates.
2. Description of the Related Art
2-Deoxy-2,2-difluoro-D-ribofuranosyl nucleosides, such as gemcitabine, have been known as therapeutic agents in viral and cancerous disease.
Processes for preparing the nucleoside agents involve the stereochemical inversion of carbohydrate intermediates bearing a leaving group at the anomeric center. Therefore, when a beta-anomer nucleoside is the desired product, an alpha-anomer enriched carbohydrate intermediate is preferably used in SN2 coupling reactions.
It has been reported that sulfonate, halide, or imidate may be used as a leaving group at the anomeric center of a carbohydrate intermediates for making nucleosides. During the reaction of the carbohydrate with a nucleobase to form a nucleoside, the leaving group on the carbohydrate intermediate is displaced with a multiply silylated derivative of a nucleobase.
The reaction can proceed by either an SN1 or an SN2 mechanism. Without using a catalyst, the reaction is typically slow. Therefore, a catalyst (typically a Lewis acid such as TMSOTf) is often used to accelerate the reaction. The reaction normally proceeds to give a protected nucleoside product with a ratio of the alpha-anomer to the beta-anomer of approximately 1:1. If an anomerically enriched starting sugar is used and an SN2 pathway is utilised, typically when a catalyst is not used, the reaction is more stereochemically selective. Nevertheless, to make a more anomerically enrich form of carbohydrate intermediate, the methods reported in the art often require additional steps and/or conditions such crystallisation or a low temperature.

There is still need for a more simple and/or efficient process for making a 2-deoxy-2,2-difluoro-D-ribofuranosyl nucleoside.